Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic condition characterized by recurrent episodes of swelling that most often affect the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts (see e.g., Banerji, Ann Allergy Asthma Immunol, 111: 329-336 (2013) and Aygoren-Pursun et al., Orphanet J Rare Dis., 9: 99 (2014)). The disease is inherited in an autosomal dominant pattern and affects 1:10,000 to 1:50,000 people. The underlying cause of HAE (type I and II) is attributed to autosomal dominant inheritance of mutations in the C1 esterase inhibitor gene (C1EI gene or SERPING1 gene), mapped to chromosome 11. Eighty-five percent of HAE cases are type I in which there is a deficiency in the amount of C1 esterase inhibitor produced (see e.g., Gower et al., World Allergy Organ J., 4: S9-S21 (2011); Cungo et al., Trends Mol Med, 15: 69-78 (2009); Gooptu et al., Annu Rev Biochem, 78: 147-176 (2009); and Zuraw et al., J Allergy Clin Immunol Pract, 1: 458-467 (2013)). The remainder of cases are characterized by the expression of a dysfunctional C1 esterase inhibitor.
The frequency, duration and severity of attacks associated with HAE vary, with 30% of patients reporting a frequency of greater than one attack/month, 40% report 6 to 11 attacks/year and the remaining 30% are infrequently symptomatic. Usually, symptoms are transient progressing over 12 to 36 hours and subsiding within 2 to 5 days; however, some attacks may last up to one week. Although HAE episodes are self-limiting, the unpredictable occurrence of attacks places considerable strain on patients, often heavily impacting quality of life, and can be fatal.
To date, therapeutic agents are indicated for long-term prophylaxis, therapy for acute attacks and short-term prophylaxis (i.e., prior to dental surgery), and include agents such as Danazol, which has a high adverse effect profile, C1 inhibitor replacement protein, bradykinin receptor antagonists, kallikrein inhibitors, fresh frozen plasma and purified C1 inhibitor. These therapies can alleviate symptoms and maximize quality of life; however, disease recurrence and the need for long-term continued administration remains a major obstacle to therapy (see e.g., Aberer, Ann Med, 44: 523-529 (2012); Charignon et al., Expert Opin Pharmacother, 13: 2233-2247 (2012); Papadopoulou-Alataki, Curr Opin Allergy Clin Immunol, 10: 20-25 (2010); Parikh et al., Curr Allergy Asthma Rep, 11: 300-308 (2011); Tourangeau et al., Curr Allergy Asthma Rep, 11: 345-351 (2011); Bowen et al., Ann Allergy Asthma Immunol, 100: S30-S40 (2008); Frank, Immunol Allergy Clin North Am, 26: 653-668 (2006); Cicardi et al., J Allergy Clin Immunol, 99: 194-196 (1997); Kreuz et al., Transfusion 49: 1987-1995 (2009); Bork et al., Ann Allergy Asthma Immunol, 100: 153-161 (2008); and Cicardi et al., J Allergy Clin Immunol, 87: 768-773 (1991)).
Thus, there is a need for a novel long-lasting therapeutic approach to treat angioedema associated with C1 esterase inhibitor deficiency. This invention provides such a therapeutic approach to treat angioedema.